Capsaicin is the pungent ingredient in chili peppers. It is a highly selective agonist for transient receptor potential vanilloid 1 receptor (TRPV1; formerly known as vanilloid receptor 1 (VR1)), a ligand-gated, non-selective cation channel preferentially expressed on small-diameter sensory neurons, especially those C-fibers which specialize in the detection of painful or noxious sensations. TRPV1 responds to noxious stimuli including capsaicin, heat, and extracellular acidification, and will integrate simultaneous exposures to these stimuli. (See: Caterina M J, Julius D. The vanilloid receptor: a molecular gateway to the pain pathway. Annu Rev Neurosci. 2001. 24:487-517). The initial effect of the activation of TRPV1-expressing (capsaicin-sensitive) nociceptors are burning sensations, hyperalgesia, allodynia, and erythema. However, after prolonged exposure to low-concentration capsaicin or single exposures to high-concentration capsaicin or other TRPV1 agonist, the small-diameter sensory axons become less sensitive to a variety of stimuli, including capsaicin or thermal stimuli. This prolonged exposure is also characterized by reduced pain responses. These later-stage effects of capsaicin are frequently referred to as “desensitization” and are the rationale for the development of capsaicin formulations for the treatment of various pain syndromes and other conditions. (See: Bley K R. Recent developments in transient receptor potential vanilloid receptor 1 agonist-based therapies. Expert Opin Investig Drugs. 2004. 13(11):1445-1456).
Capsaicin, capsaicinoids and TRPV1 agonists may be useful for amelioration of a plurality of diseases. For example, they may be used to treat neuropathic pain (including pain associated with diabetic neuropathy, postherpetic neuralgia, HIV/AIDS, traumatic injury, complex regional pain syndrome, trigeminal neuralgia, erythromelalgia and phantom pain), pain produced by mixed nociceptive and/or neuropathic mixed etiologies (e.g., cancer), osteoarthritis, fibromyalgia, lower back pain, inflammatory hyperalgesia, vulvar vestibulitis or vulvodynia, sinus polyps interstitial cystitis, neurogenic or overactive bladder, prostatic hyperplasia, rhinitis, surgery, trauma, rectal hypersensitivity, burning mouth syndrome, oral mucositis, herpes (or other viral infections), prostatic hypertrophy, dermatitis, pruritis, itch, tinnitus, psoriasis, warts, cancers (especially skin cancers), headaches, and wrinkles.
Numerous delivery devices and formulations are available or are being developed to deliver capsaicin. However, one of the problems with many of these devices and formulations is the concomitant pain (a burning sensation due to the pungency of the drug) associated with the administration of the capsaicin or other TRPV1 agonist. In addition, many of these formulations and devices are not suitable for prolonged or sustained delivery.
Accordingly, it would be desirable to provide improved delivery devices and formulations, which have the potential for reduced pungency associated with the administration of a TRPV1 agonist. In addition, it would be desirable to provide improved delivery devices and formulations that have improved dermal pharmacokinetics and prolonged or sustained delivery capability to the intended site of action. Finally, in some cases it would be desirable to deliver another pharmacologically active compound along with capsaicin, a capsaicinoid, or other TRPV1 agonist.